Transitioning from pediatric to adult-oriented healthcare in rheumatology: the pediatric side of the coin.

OBJECTIVES: The transition of adolescents and young adults (AYAs) from pediatric to adult-oriented healthcare may be affected by many factors, including the personal and cultural settings. We aimed to analyze the transition readiness and the factors affecting the transition success in rheumatology. METHODS: Patients older than 12 years were included in this prospective study. All filled out the Transition Readiness Assessment Questionnaire (TRAQ) 5.0. AYAs were phone-interviewed after their transfer to adult-oriented healthcare. Drug adherence was evaluated with 4-item Morisky Medication Adherence Scale (MMAS-4). AYAs rated their transitional care experience with visual analogue scale (VAS 0-10; 0, the worst; 10, the best). RESULTS: A total of 504 TRAQs were filled out by 406 patients (F/M = 1.5). The total TRAQ score was positively correlated with age and higher in the forms filled out by girls than boys (4.2 vs 4.0, respectively; p= 0.005). The transition was successful for 78 (83.9%) out of 93 patients transferred to adult-oriented healthcare. The VAS for the transition process was lower and the post-transfer MMAS-4 score was worse (8 vs 9, p= 0.030 and 3 vs 4, p= 0.020; respectively) in patients whose transition was not successful when compared with the successfully-transitioned ones. The best-performing TRAQ cut-off value was >4.0 for predicting transfer readiness in rheumatology. CONCLUSION: A TRAQ score of > 4 could be used while deciding about the transfer readiness of AYAs in rheumatology. Improving the AYAs' experience of the transition process and closely monitoring medication adherence during transition are essential for a successful transition.

A treatment algorithm for familial Mediterranean fever patients with menstruation-associated attacks.

OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by febrile polyserositis attacks. Menstruation could be a trigger for attacks. We aimed to analyze the features of adolescent FMF patients with menstruation-associated attacks and propose a management algorithm. METHODS: All female FMF patients who had menarche and visited the Pediatric Rheumatology Unit between January-December 2022, were included into this study. Demographics, general characteristics, and the features of menstrual cycle and FMF attacks were noted. RESULTS: A total of 151 female FMF patients were included. Thirty-five (23.2%) had menstruation-associated attacks. Fever and arthritis were less frequent during the menstruation-associated attacks than the attacks not associated with menstruation in these patients (65.7% vs 88.6%, p= 0.01 and 2.9% vs 20%, p= 0.04; respectively). Patients with menstruation-associated FMF attacks were younger at symptom onset and diagnosis (2.5 vs 5 years, p= 0.004 and 4 vs 7 years, p= 0.01; respectively), had a higher rate of dysmenorrhea (74.3% vs 38.8%, p< 0.001, respectively) and higher pre- and post-menarche attack frequency (4 vs 2 and 10 vs 0, respectively; p< 0.001 for both) than patients whose attacks were not associated with menstruation. The interventions for menstruation-associated attacks included initiating colchicine, increasing the dose of colchicine, switching from coated to compressed colchicine tablets or anti-interleukin 1 drugs, and on-demand non-steroidal anti-inflammatory drugs, on-demand glucocorticoids, and on-demand anakinra. On-demand therapies were beneficial in controlling menstruation-associated attacks. CONCLUSIONS: This is the largest cohort of adolescent FMF patients with menstruation-associated attacks. Severe FMF may cause tendency to this association. On-demand therapies could be preferred in the management.

Defining criteria for disease activity states in systemic juvenile idiopathic arthritis based on the systemic Juvenile Arthritis Disease Activity Score.

OBJECTIVE: To develop and validate cutoff values in the systemic Juvenile Arthritis Disease Activity Score 10 (sJADAS10) that distinguish the states of inactive disease (ID), minimal disease activity (MiDA), moderate disease activity (MoDA), and high disease activity (HDA) in children with systemic juvenile idiopathic arthritis (sJIA), based on subjective disease state assessment by the treating pediatric rheumatologist. METHODS: The cutoffs definition cohort was composed of 400 patients enrolled at 30 pediatric rheumatology centers in 11 countries. Using the subjective physician rating as an external criterion, 6 methods were applied to identify the cutoffs: mapping, calculation of percentiles of cumulative score distribution, Youden index, 90% specificity, maximum agreement, and ROC curve analysis. Sixty percent of the patients were assigned to the definition cohort and 40% to the validation cohort. Cutoff validation was conducted by assessing discriminative ability. RESULTS: The sJADAS10 cutoffs that separated ID from MiDA, MiDA from MoDA, and MoDA from HDA were ≤ 2.9, ≤ 10, and > 20.6. The cutoffs discriminated strongly among different levels of pain, between patients with or without morning stiffness, and between patients whose parents judged their disease status as remission or persistent activity/flare or were satisfied or not satisfied with current illness outcome. CONCLUSION: The sJADAS cutoffs revealed good metrologic properties in both definition and validation cohorts, and are therefore suitable for use in clinical trials and routine practice.

The Juvenile Arthritis Quality of Life Questionnaire in patients with juvenile idiopathic arthritis: Turkish version, validity, and reliability study.

INTRODUCTION: This study aimed to assess the cultural adaptation, validity, and reliability of the Turkish version of the Juvenile Arthritis Quality of Life Questionnaire (JAQQ) in patients with juvenile idiopathic arthritis (JIA). METHODS: A total of 100 JIA patients (64% female), aged 9 to 18 years, participated in the study conducted at a tertiary care university hospital. The JAQQ was culturally adapted through a rigorous translation process and administered alongside established measures, including the Childhood Health Assessment Questionnaire (CHAQ), Juvenile Arthritis Biopsychosocial Questionnaire (JABQ), and Children's Depression Inventory (CDI). Validity and reliability were evaluated using Spearman's correlation coefficients, Cronbach's alpha, intraclass correlation coefficient (ICC), standard error of the mean (SEM), and minimal detectable change (MDC). RESULTS: The Turkish version of JAQQ exhibited high convergent validity, correlating significantly with CHAQ, JABQ, and CDI. No floor or ceiling effects were observed in the total JAQQ score, indicating a balanced assessment. Internal consistency was excellent (Cronbach's α = 0.948), and test-retest reliability was satisfactory (ICC = 0.913). SEM and MDC95 values were 0.357 and 0.99, respectively. CONCLUSIONS: The Turkish adaptation of JAQQ emerges as a valid and reliable instrument for comprehensively assessing the health-related quality of life in children and adolescents diagnosed with JIA. The questionnaire's robust psychometric properties, coupled with distinctive features like individualized assessment, highlight its potential as a valuable tool for both clinical assessment and scientific research in the field of pediatric rheumatology. Key Points • The Juvenile Arthritis Quality of Life Questionnaire (JAQQ) is an important scale that evaluates the quality of life of children with Juvenile Idiopathic Arthritis (JIA). • JAQQ is known and used in the field of pediatric rheumatology in Turkey, but its Turkish adaptation has not been made before. • Our study includes 100 JIA patients aged between 9 and 18 years and shows that the Turkish version of JAQQ is valid and reliable in measuring the quality of life of these children. • This research contributes to the accurate assessment of the quality of life in Turkish children diagnosed with JIA, providing valuable insights for both clinical and scientific studies.

Factors determining resistance to conventional disease-modifying anti-rheumatic drug treatment in oligoarticular juvenile idiopathic arthritis.

OBJECTIVE: Our study was designed to investigate the reasons for starting the conventional disease-modifying anti-rheumatic drugs (DMARDs) and the variables that impact the response to DMARD treatment in oligoarticular juvenile idiopathic arthritis (JIA) patients. METHODS: Oligoarticular JIA patients (n = 187) were categorized into two groups: Group A consisted of patients who achieved remission with DMARD, and Group B comprised those who did not respond to DMARD therapy. RESULTS: DMARDs were initiated for various reasons: 68 (36.4%) due to active disease despite nonsteroidal anti-inflammatory drugs (± intra-articular corticosteroid) treatment, 59 (31.6%) due to uveitis, 49 (26.2%) due to extended oligoarticular JIA, and 11 (5.9%) due to inflammatory bowel disease. One hundred twenty-three patients (65.8%) achieved remission with DMARDs (Group A), while 64 patients (34.2%) did not respond to DMARD therapy (Group B). In Group B, patients had higher C-reactive protein (CRP) levels as well as higher Juvenile Idiopathic Arthritis Disease Activity Scores-71 (JADAS-71) at diagnosis (both p < 0.001). Moreover, extended oligoarticular JIA subtype (p = 0.017) and involvement of small joints at diagnosis (p = 0.043) were more prevalent among these patients. Group A exhibited a higher frequency of antinuclear antibody positivity (p = 0.014). Elevated CRP levels (> 1.1 mg/dL) (OR 1.308, 95% CI 1.203-3.574; p < 0.001) and high JADAS-71 at diagnosis (> 15.8) (OR 1.659, 95% CI 1.179-2.941; p < 0.001) were associated with DMARD resistance. CONCLUSION: Elevated CRP and high JADAS-71 at diagnosis were the main factors associated with DMARD resistance in oligoarticular JIA. Prospective long-term studies may help verify the role of these factors associated with DMARD resistance in oligoarticular JIA. Key Points • Conventional DMARDs were most commonly started due to active disease despite NSAID (± intra-articular corticosteroids). • Remission was achieved with DMARD in 65.8% of oligoarticular JIA patients. • Elevated CRP and high JADAS-71 at diagnosis were associated with DMARD resistance.

Is it possible to predict a disease course prone to macrophage activation syndrome at systemic juvenile idiopathic arthritis diagnosis?

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (SJIA). We aimed to compare the characteristics of SJIA patients who developed MAS in the disease course to those who never experienced MAS. METHODS: Patients with SJIA were included. The features of the patients at the time of SJIA diagnosis were compared. Multivariate logistic regression and ROC analyses were used while evaluating factors associated with MAS. RESULTS: Overall, 126 SJIA patients (M/F:1.17) were included. Eighty-six (68.2%) never had MAS. At the time of SJIA diagnosis, age was younger; the duration of fever was longer; rash, hepatomegaly, and splenomegaly were more frequent and arthralgia/arthritis was less common among patients who had MAS in the follow-up than those who never had MAS. Also, white blood cell, neutrophil, and platelet counts and fibrinogen were lower, while transaminases, lactate dehydrogenase, triglyceride (TG), and ferritin levels were higher among patients with MAS than those without MAS. The multivariate regression analysis disclosed age at symptom onset, duration of fever, platelet count, TG and ferritin levels as independent MAS predictors. For ferritin level/platelet count (F/P) ratio at the time of SJIA diagnosis, a threshold of ≥1.1 performed best to predict a MAS-prone disease course with a sensitivity of 90% and a specificity of 82.6%. CONCLUSION: The F/P ratio at the time of SJIA diagnosis may be a promising biomarker to predict MAS-prone disease course in SJIA. Determining MAS-prone patients at the time of SJIA diagnosis could assist physicians while tailoring SJIA treatment individually. Key points • Systemic juvenile idiopathic arthritis (SJIA) patients with macrophage activation syndrome (MAS) differ from SJIA patients who never have MAS, at the time of SJIA diagnosis. • It could be possible to predict a MAS-prone disease course at the time of SJIA diagnosis. • The ferritin/platelet ratio is a promising biomarker for predicting MAS-prone SJIA disease course.

A clinical overview of paediatric sarcoidosis: Multicentre experience from Turkey.

OBJECTIVES: We aimed to outline the demographic data, clinical spectrum, and treatment approach of sarcoidosis in a large group of patients and sought to figure out the variations of early-onset (EOS) and late-onset paediatric sarcoidosis (LOS). METHODS: The study followed a retrospective-descriptive design, with the analysis of medical records of cases diagnosed as paediatric sarcoidosis. RESULTS: Fifty-two patients were included in the study. The median age at disease onset and follow-up duration were 83 (28.2-119) and 24 (6-48) months, respectively. Ten (19.2%) cases had EOS (before 5th birthday) and 42 (80.7%) cases had LOS. The most common clinical findings at the time of the disease onset were ocular symptoms (40.4%) followed by joint manifestation (25%), dermatological symptoms (13.5%), and features related to multi-organ involvement (11.5%). Anterior uveitis was the most common (55%) one among ocular manifestations. Patients with EOS displayed joint, eye, and dermatological findings more commonly than patients with LOS. The recurrence rate of disease in patients with EOS (5.7%) and LOS (21.1%) were not statistically different (P = .7). CONCLUSIONS: Patients with EOS and LOS may present with variable clinical features and studies addressing paediatric sarcoidosis cases in collaboration between disciplines will enhance the awareness of this rare disease among physicians and assist early diagnosis with lesser complications.

A score for predicting colchicine resistance at the time of diagnosis in familial Mediterranean fever: data from the TURPAID registry.

OBJECTIVES: Colchicine forms the mainstay of treatment in FMF. Approximately 5-10% of FMF patients are colchicine resistant and require anti-IL-1 drugs. We aimed to compare the characteristics of colchicine-resistant and colchicine-responsive patients and to develop a score for predicting colchicine resistance at the time of FMF diagnosis. METHODS: FMF patients (0-18 years) enrolled in the Turkish Paediatric Autoinflammatory Diseases (TURPAID) registry were included. The predictive score for colchicine resistance was developed by using univariate/multivariate regression and receiver operating characteristics analyses. RESULTS: A total of 3445 FMF patients [256 (7.4%) colchicine-resistant and 3189 colchicine-responsive) were included (female:male ratio 1.02; median age at diagnosis 67.4 months). Colchicine-resistant patients had longer, more frequent attacks and were younger at symptom onset and diagnosis (P < 0.05). Fever, erysipelas-like erythema, arthralgia, arthritis, myalgia, abdominal pain, diarrhoea, chest pain, comorbidities, parental consanguinity and homozygosity/compound heterozygosity for exon 10 MEFV mutations were significantly more prevalent among colchicine-resistant than colchicine-responsive patients (P < 0.05). Multivariate logistic regression analysis in the training cohort (n = 2684) showed that age at symptom onset, attack frequency, arthritis, chest pain and having two exon 10 mutations were the strongest predictors of colchicine resistance. The score including these items had a sensitivity of 81.3% and a specificity of 49.1%. In the validation cohort (n = 671), its sensitivity was 93.5% and specificity was 53.8%. CONCLUSION: We developed a clinician-friendly and practical predictive score that could help us identify FMF patients with a greater risk of colchicine resistance and tailor disease management individually at the time of diagnosis.

Feasibility of canakinumab withdrawal in colchicine-resistant familial Mediterranean fever.

OBJECTIVES: There is no consensus on canakinumab treatment tapering and discontinuation strategies in colchicine-resistant FMF patients. In this study, we aimed to establish a treatment management and discontinuation protocol in paediatric FMF patients treated with canakinumab. METHODS: Fifty-eight FMF patients treated with canakinumab were included. Since 2020, we have applied a protocol based on our experience whereby canakinumab is administered monthly in the first 6 months, followed by bimonthly for 6 months, and a final period of every 3 months (for 6 months). The patients were divided into two groups: 2012-2019 (group A) and 2020-2022 (group B). RESULTS: In group A (n = 33), the median duration of canakinumab treatment was 2.5 years [interquartile range (IQR) 1.9-3.7]. A total of 25 of 33 patients discontinued canakinumab after a median of 2.1 years (IQR 1.8-3.4). In two patients, canakinumab was restarted because of relapse. In group B (n = 25), canakinumab was discontinued in 18 patients at the end of 18 months. After a median follow-up of 0.8 years (IQR 0.6-1.1), two patients had a relapse and canakinumab treatment was reinitiated. The remaining 16 patients still have clinically inactive disease and are receiving only colchicine. When we compared the characteristics between groups A and B, there were no significant differences regarding demographics, clinical features, and outcomes. CONCLUSION: This is the largest study in the literature suggesting a protocol for discontinuing canakinumab in paediatric FMF patients. It was possible to discontinue canakinumab successfully in more than half of the patients in 18 months. Thus we suggest that this protocol can be used in paediatric FMF patients.

Patients Without a Rheumatic Disease Diagnosis in a Pediatric Rheumatology Unit: Retrospective Analysis and Comparison Between Pre-pandemic and Pandemic Periods.

OBJECTIVE: Children with suspicious complaints of rheumatic diseases are generally referred to a pediatric rheumatologist. We aimed to evaluate the profile of patients referred to the pediatric rheumatology unit and were not diagnosed with a rheumatic disease and to assess the impact of the coronavirus disease-2019 pandemic on referral complaints. MATERIALS AND METHODS: All new outpatients who applied to the pediatric rheumatology department between March 2019 and February 2021 and were not diagnosed with rheumatic disease were included. We also compared the frequency of admission symptoms during the pre-pandemic (March 2019-February 2020) and pandemic periods (March 2020-February 2021). RESULTS: A total of 1089 patients without a rheumatic disease diagnosis (568 female, 52.2%; median age 10.0 years) were included in this study. The most common complaint for referral was prolonged or recurrent fevers (13.4%) followed by anti-nuclear antibody positivity (13.1%), arthralgia (13.0%), skin findings (7.5%), and the presence of heterozygous mutations in the Mediterranean fever gene (6.9%). During the pandemic year, the number of patients referred for back pain increased significantly (P = .028). A total of 682 of 1089 patients were consulted from other departments in our center (62.6%). Of these, the most frequent consultation request was from general pediatrics (43.6%). The rheumatic disease was excluded in 11.3% of the patients. CONCLUSION: Prolonged or recurrent fever and anti-nuclear antibody positivity were the most frequent complaints of referrals to a pediatric rheumatology unit in patients who did not have a rheumatic disease. The rate of back pain was more common in children during the pandemic period.

Cardiovascular manifestations of monogenic periodic fever syndromes.

Periodic fever syndromes (PFS) are a group of autoinflammatory diseases characterized by repeated febrile episodes and systemic inflammation. The most common monogenic periodic fever syndromes are familial Mediterranean fever, mevalonate kinase deficiency/hyper immunoglobulin D syndrome, cryopyrin-associated periodic syndrome, and tumor necrosis factor receptor-associated periodic syndrome. Although fever is the predominant feature of PFS, other systems, including the cardiovascular system, may be involved in the disease process. This review focuses on cardiovascular risks and issues in monogenic PFS. Cardiovascular involvement may occur as a disease manifestation, association, or result of complications or a drug's adverse effects in monogenic PFS. Pericarditis seems to be a feature of PFS. Patients with recurrent pericarditis or pericarditis resistant to conventional treatment should be evaluated for PFS. Amyloidosis is the most severe complication of PFS, increasing the risk of cardiac morbidity. Furthermore, ongoing inflammation may result in early atherosclerosis. Therefore, assessing cardiovascular risks in PFS patients should be considered a part of routine care. Key points • Pericarditis is the most common cardiac involvement of monogenic periodic fever syndromes (PFS), while some forms may present with myocarditis. • Amyloidosis, the most significant complication of PFS, may lead to deterioration in cardiac functions. • Ongoing inflammation in PFS may result in endothelial dysfunction and atherosclerosis. • Effective control of inflammation and reducing concomitant risk factors such as obesity, diabetes mellitus, and hypertension could improve cardiovascular outcomes in PFS patients.

Report of 2 pediatric cases with atypical Cogan's syndrome and a systematic review.

Cogan's syndrome (CS) is a rare inflammatory disease characterized by interstitial keratitis or uveitis, vestibular impairment, and progressive hearing loss, commonly bilateral. Although glucocorticoids are fundamental treatment options, in most cases, hearing loss gradually worsens. Herein we report 2 pediatric cases of CS who were treated with corticosteroids and methotrexate. One patient had a cochlear implant, and the hearing of the other patient improved with treatment. Also, a systematic literature review was conducted for articles including pediatric CS patients. In the literature, 34 articles describing 44 pediatric patients with CS were identified. Sudden hearing loss (95.3%) and ocular symptoms (92.5%) were the most common manifestations in these patients. Also, aortic involvement was present in 19.5% of patients in the literature. Otorhinolaryngologists, ophthalmologists, and pediatricians should collaborate to diagnose and manage CS to prevent progressive hearing loss and eye involvement.

Rice bodies in children with rheumatic disorders: A case series and systematic literature review.

OBJECTIVES: Rice body (RB) formation is an uncommon inflammatory process seen in systemic disorders. In this study, we aimed to assess characteristic features of RBs in pediatric patients. METHOD: We retrospectively evaluated pediatric patients who underwent joint/extremity magnetic resonance imaging. A systematic literature review was conducted for articles including children with RBs. RESULTS: We found 24 patients (median age 6.1 years; F/M = 2.4) with RBs [23 with juvenile idiopathic arthritis (JIA) and one with arthralgia]. The most prevalent location for RBs was the knee joint (75%). RBs were most frequently seen as diffuse multiple millimetric structures. In three out of five patients with follow-up magnetic resonance imaging, resolution or regression of RBs was observed without surgical intervention. Our literature search identified 13 pediatric patients with RBs. Most (84.6%) had JIA, and the knee joint (71.4%) was the most commonly affected joint. Surgery was preferred in our 3 patients (12.5%) and 10 literature patients (83.3%) in the treatment. CONCLUSION: Our results showed that RBs were most commonly detected in the knee joint, and most cases were secondary to JIA. Although surgery is used as a treatment option, we observed that RBs can occasionally disappear during follow-up without surgical intervention.

Choice and switch of biologic drugs in juvenile idiopathic arthritis.

BACKGROUND: In this study, we aimed to evaluate choices and changes of biologic drugs in juvenile idiopathic arthritis (JIA) patients according to disease subtypes. METHODS: We retrospectively analyzed JIA patients who received biologic treatment between January 2004 and July 2022. RESULTS: Of 294 JIA patients, 80 (27.2%) had systemic JIA, 68 (23.1%) had oligoarticular JIA, 61 (20.7%) had polyarticular JIA, 79 (26.9%) had enthesitis-associated arthritis (ERA), and six (2.1%) had psoriatic arthritis (PsA). Anakinra (n=66, 82.5%) was the most commonly preferred first line biologic in systemic JIA. Etanercept was the most frequently used biologic drug in patients with ERA (n=69, 87.3%), oligoarticular (n=37, 54.4%) and polyarticular JIA (n=43, 70.5%). Adalimumab was used as a first-line biologic drug in all PsA patients (n=6, 100%). One hundred-fourteen patients (38.8%) were switched to second-line and 29 (9.9%) to third-line biologic drugs. While the most common reason for switching to a second-line biologic was difficulty in usage of daily injections (n=37, 60.6%) in systemic JIA patients, it was an inadequate response to first biologics in non-systemic JIA patients (n=42, 79.2%). Side effects were detected in only seven patients (2.4%) during the follow-up. CONCLUSION: In this study, we revealed the biologic drug usage and switch strategies in our JIA patients. Good responses were obtained in most of our patients with a reliable profile. However, studies on larger patient groups are needed to clarify these results.

Treatment of childhood-onset Takayasu arteritis: switching between anti-TNF and anti-IL-6 agents.

OBJECTIVES: Biologics are new treatment alternatives in Takayasu arteritis (TA), although data in childhood are limited. The aim of this study was to share our experience in seven childhood-onset TA patients who received a TNF-α inhibitor (adalimumab) or an IL-6 receptor inhibitor (tocilizumab) and the effect of switching therapy. METHODS: We retrospectively evaluated the medical treatment records of seven patients with TA, followed between August 2005 and January 2021 at the Pediatric Rheumatology Department of Hacettepe University Faculty of Medicine. RESULTS: The median age of patients was 14 (IQR 4) years, and six were female. All of the patients had severe disease and high acute-phase reactants. The patients initially received only steroids or steroids+CYC. Prednisone was decreased, and biologic agents were started once the acute phase reactants decreased, and the Indian Takayasu Activity Score (ITAS) returned to normal. Initially, four patients received tocilizumab (TCZ) [median 25.5 (IQR 41) months] and three patients received adalimumab (ADA) [median 13 (IQR 31) months]. However, due to the progression of MR angiography findings or persistent elevation in acute-phase reactants, the biologic agents were switched from TCZ to ADA in four patients and from ADA to TCZ in three patients. The patients' median follow-up time after changing was 50 (IQR 77) months, and median ITAS was evaluated as '0' after 2 (IQR 4) months. CONCLUSIONS: In conclusion, both TNF-α and IL-6 inhibitors are effective alternatives in treating patients with childhood-onset TA. However, prospective randomized controlled trials are needed for the comparison of their effectiveness.

Colchicine and Leukopenia: Clinical Implications.

Colchicine is the mainstay of treatment for familial Mediterranean fever. We investigated the frequency of leukopenia in 213 patients with familial Mediterranean fever treated with standard doses of colchicine (0.5-2.0 mg/day). We found that 23 patients (10.8%) had reversible leukopenia, 3 moderate, and none severe and that their rate of infections was not increased.